The molecular physiology of the axo-myelinic synapse

Exp Neurol. 2016 Feb;276:41-50. doi: 10.1016/j.expneurol.2015.10.006. Epub 2015 Oct 26.


Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis.

Keywords: AMPA; Action potential; Axons; Ca(2+) imaging; Myelin; NMDA; Ryanodine receptor; Vesicular release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology*
  • Axons / ultrastructure
  • Calcium Signaling / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Myelin Sheath / physiology*
  • Myelin Sheath / ultrastructure
  • Nerve Fibers, Myelinated / physiology*
  • Nerve Fibers, Myelinated / ultrastructure
  • Optic Nerve / physiology*
  • Optic Nerve / ultrastructure
  • Rats
  • Rats, Long-Evans
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Synapses / physiology*
  • Synapses / ultrastructure


  • Receptors, N-Methyl-D-Aspartate